Abstract:
BACKGROUND AIMS:Chimeric antigen receptors (CARs) designed for adoptive immunotherapy need to achieve two functions: antigen recognition and triggering of the lytic machinery of reprogrammed effector cells. Cytotoxic T cells have been engineered with FcγRIII (CD16) chimeric molecules to be redirected against malignant cells by monoclonal antibodies (mAbs). These cells have been proven to mediate granule-dependent cellular cytotoxicity, but it is not clear whether they can also kill malignant cells by a granule-independent mechanism of cell cytotoxicity. METHODS:We engineered a CD16A-CAR equipped with the extracellular CD16A, the hinge spacer and the transmembrane region of CD8, and the ζ-chain of the T-cell receptor/CD3 complex in tandem with the CD28 co-stimulatory signal transducer module. The CD16A-CAR was expressed and functionally tested in the MD45 cell line, a murine T-cell hybridoma with a defective granular exocytosis pathway but capable of killing target cells by a Fas ligand-mediated lysis. RESULTS:Our results indicate that in vitro cross-linking of CD16A-CAR on MD45 cells by the Fc fragment of mAb opsonized tumor cells induced interleukin-2 release and granule-independent cellular cytotoxicity. CONCLUSIONS:We conclude that strategies aimed to implement the therapeutic functions of mAbs used in the clinic with T-dependent immune responses driven by engineered T cells expressing FcγR-CAR can boost the antitumor efficacy of mAbs used in the clinic.
journal_name
Cytotherapyjournal_title
Cytotherapyauthors
D'Aloia MM,Caratelli S,Palumbo C,Battella S,Arriga R,Lauro D,Palmieri G,Sconocchia G,Alimandi Mdoi
10.1016/j.jcyt.2015.10.014subject
Has Abstractpub_date
2016-02-01 00:00:00pages
278-90issue
2eissn
1465-3249issn
1477-2566pii
S1465-3249(15)01119-6journal_volume
18pub_type
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